Assessment of safety, cardiovascular and subjective effects after intravenous cocaine and lofexidine

Abstract

The primary objective of this study was to determine the safety of lofexidine, an α2 receptor agonist, alone and concurrent with cocaine in non-treatment seeking cocaine-dependent or cocaine-abusing participants. After screening, eligible participants received double-blind, randomized infusions of saline and 20 mg of cocaine on Day 1, and saline and 40 mg of cocaine on Day 2. Subjects were randomized and started receiving daily administration of placebo (N=4) or lofexidine on Day 3 and continued on this schedule until Day 7. Two dosing regimens for lofexedine were investigated: 0.8 QID (N=3) and 0.2 mg QID (N=11). On Days 6 and 7, subjects received double-blind infusions of saline and 20 mg of cocaine on Day 6, and saline and 40 mg of cocaine on Day 7. The data reveal a notable incidence of hemodynamic-related AEs over the course of the study. Two of the three participants at the 0.8 mg dose level discontinued, and five of 11 participants at the 0.2 mg dose level were withdrawn (or voluntarily discontinued) after hemodynamic AEs. Subjective effects and cardiovascular data were derived from all participants who were eligible to receive infusions (i.e., did not meet stopping criteria) on Days 6 and 7 (6 received lofexidine 0.2 mg, QID and 4 received placebo, QID). As expected, cocaine significantly increased heart rate and blood pressure, as well as several positive subjective effects. There was a trend for lofexidine to decrease cocaine-induced cardiovascular changes and cocaine-induced ratings for "Any Drug Effect", "Good Effects", and “Desire Cocaine”, but sample size issues limit the conclusions that can be drawn. Despite the trends to reduce cocaine-induced subjective effects, cardiovascular AEs may limit future utility of lofexidine as a treatment for this population.

Evaluation of the dopamine β-hydroxylase (DβH) inhibitor nepicastat in participants who meet criteria for cocaine use disorder

“…To this end, we evaluated the potential for nepicastat to alter the subjective effects produced by cocaine. As demonstrated previously (De La Garza et al, 2014; Hameedi et al, 1995; Newton et al, 2005; Verrico et al, 2014), acute cocaine exposure in this study increased several positive subjective effects. Analyses revealed a main effect of nepicastat to reduce several cocaine-induced positive subjective effects, though the cocaine by nepicastat interaction did not reach statistical significance.…”

Altered methamphetamine place conditioning in mice vaccinated with a succinyl-methamphetamine-tetanus-toxoid vaccine

“…Potential pharmacotherapies are often complicated by serious drug interactions or poor medication side-effect profiles that decrease compliance and thus efficacy when assessed in clinical trials. [3][4][5] An alternative treatment approach for SUDs is immunotherapy that has better compliance since treatments may involve fewer adverse events and only a few injections instead of daily medication dosing. [6][7][8] A number of SUD vaccines are in preclinical development, and some have been tested in humans.…”